Asai Toshihiro, Nakatani Tatsuya, Tamada Satoshi, Kuwabara Nobuyuki, Yamanaka Shinya, Tashiro Koichiro, Nakao Takafumi, Komiya Toshiyuki, Okamura Mikio, Kim Shokei, Iwao Hiroshi, Miura Katsuyuki
Department of Urology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
Transplantation. 2003 Apr 15;75(7):1040-4. doi: 10.1097/01.TP.0000057242.96219.AF.
It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors.
CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay.
DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28.
Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.
已有研究表明，转录因子激活蛋白（AP）-1和核因子（NF）-κB在多种肾脏疾病中起关键作用。我们旨在研究它们在慢性环孢素A（CsA）肾毒性中的激活情况，并评估补充镁（Mg）和阻断肾素-血管紧张素系统（RAS）（已知可改善CsA肾毒性）对这些转录因子的影响。
将CsA（15毫克/千克/天）皮下注射给维持低钠饮食的大鼠，持续7、14和28天。通过电泳迁移率变动分析测定肾皮质中AP-1和NF-κB的DNA结合活性。
CsA处理后，AP-1和NF-κB的DNA结合活性在第14天开始增加，并在第28天进一步升高。当大鼠维持高镁饮食时，这些激活明显减弱。相比之下，血管紧张素转换酶抑制剂（ACEI）对CsA诱导的AP-1激活没有影响。在第14天，ACEI可抑制CsA诱导的NF-κB激活，而在第28天未观察到这种作用。
在慢性CsA肾毒性中，肾皮质AP-1和NF-κB的DNA结合被激活。这些激活主要通过不依赖RAS的机制诱导。提示预防CsA诱导的这些转录因子的DNA结合激活至少部分是补充Mg对CsA肾毒性产生有益作用的原因。
